The overall objective of this proposal is to improve the clinical care of human immunodeficiency virus (HIV)-infected, alcohol-using patients by identifying significant interactions which may occur between drugs commonly used to treat HIV disease known to be cytochrome P450 (CYP450) inducers or inhibitors and alcohol, the most frequently abused substance in the United States. We hypothesize that concomitant use of alcohol and currently utilized highly active antiretroviral therapy (HAART) will be associated with significant drug interactions including alteration of alcohol and ARV pharmacokinetics as well as altered responses to alcohol administration. Certain ARV that are frequent components of HAART are inducers of CYP 450 enzymes (e.g.: the non-nucleoside reverse transcriptase inhibitor, efavirenz), while others are known to inhibit CYP 450 enzyme function (e.g.: protease inhibitors; particularly ritonavir which is frequently co-administered with other protease inhibitors to delay their metabolism). Furthermore, chronic alcohol abuse is known to induce CYP450 enzymes, including CYP 3A4, which could contribute further to the potential for hepatotoxicity in those maintained on ARV. We plan to conduct alcohol and HAART administration studies to four study samples (n=10 each): 1.those with HIV/AIDS or and eligible for efavirenz-containing HAART, 2. those with HIV/AIDS and eligible for a ritonavir-boosted protease inhibitor based HAART, 3. those with HIV/AIDS and Hepatitis C eligible for an efavirenz-containing HAART or 4. eligible for a ritonavir-boosted protease inhibitor regimen. Study sessions will include alcohol or placebo administration followed by alcohol or placebo administration with the HAART of interest. Pharmacokinetics, subjective, and cognitive data will be serially collected over the course of the study sessions. Data collected will elucidate the presence and clinical significance of drug interactions, both pharmacokinetic and pharmacodynamic, between alcohol and HAART in these populations. These findings will provide new and important information directly applicable to enhancing the clinical care of this population. [unreadable] [unreadable] PUBLIC HEALTH RELEVANCE: Liver toxicity in HIV disease is a common occurrence and may be related to multiple etiologies including pre-existing liver disease, toxicities from treatment of HIV/AIDS and/or toxicity related to alcohol consumption. Co-occurrence of Hepatitis C is present in up to 30% of patients with HIV/AIDS and liver disease is now the second most common cause of death in those with HIV disease. These facts underscore the need to understand drug interactions that may occur between HIV therapeutics and alcohol. This project will undertake drug interaction studies of the effect of alcohol alone and in combination with highly active antiretroviral therapy (HAART) in those with HIV/AIDS and HIV/AIDS and Hepatitis C in order to illuminate the clinically significant pharmacokinetic and pharmacodynamic interactions that may occur. The urgent need to provide effective treatment to those with HIV/AIDS requires that we study the impact of concomitant use of alcohol with HAART which could potentially produce adverse drug interactions and/or alter the efficacy of these medications. The proposed studies will inform clinical treatment of comorbid HIV/AIDS, Hepatitis C and alcohol use/abuse leading to improved clinical outcomes and reduced risk of HIV transmission. [unreadable] [unreadable] [unreadable]